The present invention relates to the use of orexin receptor antagonists as neuroprotectants, and in the treatment of nausea and vomiting, irritable bowel syndrome and other conditions associated with visceral pain.
Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers.
Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in U.S. Pat. Nos. 5,935,814, 6,020,157 and 6,410,701. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in U.S. Pat. No. 6,166,193.
Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed in U.S. Pat. No. 6,309,854.
Orexin receptors are found in the mammalian host and may be responsible for many biological functions.
Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.
Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.
Orexin-1 receptor mRNA and immunoreactivity is widely distributed throughout the brain including regions such as the hypothalamus, hippocampus and various other limbic and cortical areas. Thus the receptor is found in brain areas which have been reported to be affected by stroke in man and experimental stroke animals and head injury in man and experimental animals, to be involved in emesis and to be involved in visceral pain.
U.S. Pat. Nos. 6,410,529 and 6,372,757 disclose various phenyl urea derivatives as orexin receptor antagonists.
It has now been discovered that compounds possessing orexin receptor antagonist activity, in particular orexin-1 receptor antagonist activity, also demonstrate neuroprotectant properties. Therefore, such compounds are useful in the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events in mammals, such as humans, including cerebral ischaemia after cardiac arrest, stroke and multi-infarct dementia, cerebral ischaemic events such as those resulting from surgery and/or during childbirth, and disorders resulting from traumatic head injury and subsequent haemorrhaging.
In particular the compounds are useful in the treatment and/or prophylaxis of stroke (ischaemic or haemorrhagic) or sub-arachnoid haemorrhage e.g. sub-arachnoid haemorrhage associated with traumatic head injury.
It has also been discovered that compounds possessing orexin receptor antagonist activity, in particular orexin-1 receptor antagonist activity, are useful for blocking the emetic response. The compounds are therefore of use in the treatment of nausea and vomiting associated with cancer therapy. The compounds are also of potential use in the treatment of post-operative or motion sickness.
It has also been discovered that compounds possessing orexin receptor antagonist activity, in particular orexin-1 receptor antagonist activity, may inhibit pain via an action on the peripheral C-fibres and are therefore useful in the treatment of conditions associated with visceral pain, such as irritable bowel syndrome and also migraine, angina and urge type incontinence such as inappropriate urge type incontinence associated with cystitis.
The present invention provides the use of an orexin receptor antagonist in the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events, the treatment and/or prophylaxis of nausea and vomiting, or the treatment and/or prophylaxis of irritable bowel syndrome or other conditions associated with visceral pain.
The present invention also provides a method for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischaemic events, the treatment and/or prophylaxis of nausea and vomiting, or the treatment and/or prophylaxis of irritable bowel syndrome or other conditions associated with visceral pain in mammals which comprises administering to a host in need thereof an effective amount of an orexin receptor antagonist or a pharmaceutically acceptable salt thereof.
When used in therapy, the orexin receptor antagonists are usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.
The orexin receptor antagonist is preferably an orexin-1 receptor antagonist.
Orexin receptor antagonists may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
Orexin receptor antagonists which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard A carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
The dose of the orexin receptor antagonist used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However as a general rule suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg; such unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months.
All U.S. patents cited in this specification are herein incorporated by reference as if each individual patent was specifically and individually indicated to be incorporated by reference herein as though fully set forth.